Prescribing information For Healthcare Professionals Only

Darzalex®

20 mg/ml concentrate
for solution for infusion

PRESCRIBING INFORMATION

Active Ingredient(s):

Daratumumab

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Indications(S): 

Newly diagnosed multiple myeloma: In combination with bortezomib, melphalan and prednisone in adults ineligible for autologous stem cell transplant

Relapsed/Refractory multiple myeloma: Monotherapy for adults, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on last therapy. In combination with lenalidomide/dexamethasone or bortezomib/dexamethasone in adults who have received ≥ one prior therapy.

Dosage & Administration:

Administration by healthcare professional where resuscitation facilities available. 
Dilute with sodium chloride 0.9% solution for injection and administer by intravenous infusion using incremental escalation of infusion rate only if previous infusion well-tolerated. 
Adults: Newly diagnosed multiple myeloma: Combination with bortezomib, melphalan and prednisone (6 week cycle): 16 mg/kg body weight weekly for 6 weeks followed by every 3 weeks up to Week 54, then every 4 weeks from Week 55, until disease progression. Relapsed/Refractory multiple myeloma: Monotherapy and combination with lenalidomide (4 week cycle): 16 mg/kg body weight weekly for 8 weeks followed by every 2 weeks up to Week 24, then every 4 weeks from Week 25. Combination with bortezomib (3 week cycle): 16 mg/kg body weight weekly for 9 weeks followed by every 3 weeks up to Week 24, then every 4 weeks from Week 25. First prescribed dose: To facilitate administration, the first prescribed 16 mg/kg dose at Week 1 may be split over two consecutive days i.e. 8 mg/kg on Day 1 and Day 2 respectively. Refer to SmPC for further details.


Recommended concomitant medications for management of infusion-related reactions (IRRs): To reduce risk, administer pre-infusion medications to all patients 1-3 hours prior to every infusion: i.e corticosteroid (monotherapy: methylprednisolone (or equivalent) iv then iv or oral from second infusion; combination: dexamethasone (or equivalent) iv then iv or oral following second infusion) plus oral antipyretics and oral or intravenous antihistamine. If dexamethasone given on infusion day, do not take additional background regimen specific corticosteroids (e.g. prednisone). To reduce the risk of delayed IRRs administer post-infusion oral corticosteroid: monotherapy e.g. mg methylprednisolone on each of two days following all infusions; combination: mg methylprednisolone the day after infusion, but may not be needed if dexamethasone or prednisone continued. Consider short/long acting bronchodilators and inhaled corticosteroids in patients with history of obstructive pulmonary disorder. Any grade/severity IRRs, interrupt Darzalex® immediately and manage symptoms. Re-starting Darzalex®: reduce infusion rate (refer to SmPC); Grade 4 IRRs - (or third occurence of Grade 3) - permanently discontinue. No dose reductions of DARZALEX® recommended. For haematological toxicity dose delay may be required to allow recovery of blood cell counts. Consider anti-viral prophylaxis for prevention of herpes zoster virus reactivation.
Children: No data available. 
Elderly/Renal impairment/Hepatic impairment: No dose adjustments.

Contraindications:

Hypersensitivity to active substance or excipients.

Special warnings & Precautions:

IRRs: Symptoms predominantly include nasal congestion, cough, throat irritation, chills, vomiting and nausea; can cause serious IRRs including anaphylactic reactions. Monitor for IRRs throughout the infusion. For any Grade of IRR, continue monitoring post-infusion until symptoms resolve. Majority occurred at first infusion; interrupt Darzalex® for any severity IRRs (see also Dosage and Administration). Institute medical management/supportive treatment as needed. If an anaphylactic reaction or life-threatening (Grade 4) IRR occurs, initiate appropriate emergency resuscitation immediately and discontinue Darzalex immediately and permanently. Neutropenia/Thrombocytopenia: Darzalex may increase neutropenia and thrombocytopenia induced by background therapy; monitor for infections & periodic complete blood cell counts (refer to relevant SmPCs); consider supportive care. Indirect Antiglobulin Test (Indirect Coombs Test): Binds to CD38; may mask detection of antibodies to minor antigens; ABO and Rh blood typing not impacted.

Interference may occur up to 6 months post-treatment. Type and screen patients prior to starting daratumumab; consider phenotyping; red blood cell genotyping not affected by daratumumab. Inform blood transfusion centres when appropriate. If emergency transfusion required, give non-cross-matched ABO/RhD-compatible RBCs. Hepatitis B virus (HBV) reactivation: Fatal cases reported in patients treated with Darzalex. Perform HBV screening before initiation of treatment. Suspend treatment in patients who develop reactivation of HBV while on Darzalex. Contains sodium.

Side Effects:

Very common: IRRs, pneumonia, upper respiratory tract infection, anaemia, neutropenia, thrombocytopenia, lymphopenia, peripheral sensory neuropathy, headache, hypertension, cough, dyspnoea, nausea, diarrhoea, vomiting, muscle spasms, fatigue, pyrexia, peripheral oedema.
Common: influenza, atrial fibrillation, pulmonary oedema.  
Other side effects: HBV reactivation (uncommon), anaphylactic reaction (rare)
Refer to SmPC for other side effects.

Pregnancy:

Effective contraception during and for 3 months after treatment in women of child-bearing potential. Do not use during pregnancy unless benefits outweigh potential risks to foetus.

Lactation:

Not known if daratumumab is excreted into breast milk.

Interactions:

No studies performed. Not anticipated to alter drug-metabolising enzymes. Daratumumab binds to CD38 on RBCs and interferes with compatibility testing (including antibody screening and cross matching). Interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or other locally validated methods. However, Kell-negative units should be supplied after ruling out/identifying alloantibodies using DTT-treated RBCs. Alternatively, consider phenotyping or genotyping. Daratumumab detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays; can impact determination of complete response and disease progression in some patients. Considerusing a validated daratumumab-specific IFE assay to facilitate determination of a complete response in patients with persistent very good partial response.
Refer to SmPC for full details of interactions.

LEGAL CATEGORY: POM

PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S) & BASIC NHS COSTS

Presentations Pack Sizes Marketing Authorisation Number(s) Basic Nhs Costs
5 ml vial (100mg daratumumab) X 1 EU/1/16/1101/001 £360
20 ml vial (400mg daratumumab) X 1 EU/1/16/1101/002 £1,440

MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV. Turnhoutseweg 30, B-2340 Beerse, Belgium

FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK.

Prescribing information last revised: June 2019


VELCADE®

3.5 mg powder for solution for injection

PRESCRIBING INFORMATION

ACTIVE INGREDIENT(S):

Bortezomib

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

The VELCADE® SmPCs are available at: 

Please click the following product name to access the full SmPC
VELCADE® 3.5mg powder for solution for injection

INDICATION(S):

Adults only. Monotherapy or with pegylated liposomal doxorubicin or dexamethasone: progressive multiple myeloma in patients who have had at least 1 prior therapy and already undergone/are not suitable for haematopoietic stem cell transplant. With melphalan & prednisone: for previously untreated multiple myeloma in patients not eligible for high-dose chemotherapy with haematopoietic stem cell transplant. With dexamethasone, or with dexamethasone and thalidomide: for induction treatment of previously untreated multiple myeloma in patients eligible for high-dose chemotherapy with haematopoietic stem cell transplant. With rituximab, cyclophosphamide, doxorubicin and prednisone: for previously untreated mantle cell lymphoma (MCL) in patients unsuitable for haematopoietic stem cell transplantation.

DOSAGE & ADMINISTRATION:

Adults and Elderly: Administer as 3-5 second IV bolus or SC in thighs/abdomen. At least 72 hours between consecutive doses. Recommended dose 1.3mg/m2 body surface area. Posology modifications required for VELCADE®-related toxicity, refer to SmPC.

Treatment of progressive multiple myeloma (after at least 1 prior therapy)
VELCADE® treatment cycle: twice weekly for 2 weeks in 21-days treatment cycle. Two cycles of VELCADE® recommended following confirmation of complete response. Responding patients without complete remission should receive total of 8 cycles.
Monotherapy: as above.
Combination with pegylated liposomal doxorubicin: 30 mg/m2 pegylated liposomal doxorubicin (1h IV infusion) on day 4 of VELCADE® treatment cycle. Combination with dexamethasone: 20 mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of VELCADE® treatment cycle.

Previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplant
Combination with oral melphalan (9mg/m2) and prednisone (60mg/m2): 9 x 6-weeks treatment cycles.

Previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplant (induction therapy)
Combination with oral dexamethasone (40mg): 4 x 21-days treatment cycles.
Combination with oral dexamethasone (40mg) and thalidomide (50mg): 4 x 28-days treatment cycles. At least partial responders: 2 additional cycles. For other medicinal products, see appropriate SmPCs.

Previously untreated mantle cell lymphoma not suitable for haematopoietic stem cell transplantation
Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP): 6 - 8 x 21-days treatment cycles. (For other medicinal products, see appropriate SmPCs.)

Children: No recommendation on posology can be made; refer to SmPC for current available data.
Hepatic Impairment: mild - no dose adjustment; moderate or severe - start on reduced dose of 0.7 mg/m2 per injection for first cycle, then possible increase to 1.0 mg/m2 or reduction to 0.5 mg/m2 based on tolerability.
Renal Impairment: See precautions.

CONTRAINDICATIONS:

Hypersensitivity to active substance, boron or any excipients. Acute diffuse infiltrative pulmonary and pericardial disease.

SPECIAL WARNINGS & PRECAUTIONS:

Do not administer intrathecally.
Monitor complete blood counts; consider platelet transfusion. GI toxicity very common; monitor closely.
In MCL, transient neutropenia reported between cycles; monitor for signs/symptoms of infection, treat promptly; consider prophylactic granulocyte colony stimulating factors if delayed cycles. Herpes zoster virus reactivation: anti-viral prophylaxis recommended. Screen for Hepatitis B Virus reactivation/infection when rituximab combination; consider antiviral prophylaxis (see SmPC for rituximab). Very rarely John Cunningham virus infection resulting in Progressive Multifocal Leukoencephalopathy (PML) and death; monitor regularly for PML symptoms, discontinue if diagnosed. Peripheral neuropathy common; requires careful monitoring, neurological evaluation and possible dose/schedule modification, or change to SC route. Special care if risk factors for seizures. Caution when history of syncope with medicinal products linked with hypotension, or dehydration due to recurrent diarrhoea/vomiting. Discontinue treatment if Posterior Reversible Encephalopathy Syndrome (PRES) occurs. Development/exacerbation of congestive heart failure/QT prolongation; monitor closely if cardiac risk factors. Renal impairment common; monitor closely. Rarely acute diffuse infiltrative pulmonary disease of unknown aetiology e.g. pneumonitis, interstitial pneumonia, lung infiltration and acute respiratory distress syndrome (ARDS); baseline chest radiograph recommended. If new/worsening pulmonary symptoms perform prompt diagnostic evaluation and treat appropriately; consider benefit/risk ratio before continuing.

Immunocomplex-mediated reactions e.g. serum sickness, polyarthritis with rash, proliferative glomerulonephritis: discontinue if severe. Bortezomib exposure increased in moderate/severe hepatic impairment; reduce doses, closely monitor. Patients with high pre-treatment tumour burden at risk of tumour lysis syndrome; monitor closely. Concomitant CYP3A4-inhibitors: monitor closely. Caution with CYP3A4 or CYP2C19 substrates.

SIDE EFFECTS:

Very common: thrombocytopenia, neutropenia, anaemia, decreased appetite, neuropathies, peripheral sensory neuropathy, dysaesthesia, neuralgia, nausea, vomiting, diarrhoea, constipation, fatigue, pyrexia, asthenia.
Multiple Myeloma: musculoskeletal pain.
MCL: pneumonia, febrile neutropenia, leukopenia, lymphopenia, stomatitis, hair disorder.

Common: herpes zoster (inc disseminated & ophthalmic), herpes simplex, fungal infection, hypokalaemia, hyponatraemia, blood glucose abnormal, sleep disorders & disturbances, motor neuropathy, loss of consciousness (inc syncope), dizziness, dysgeusia, vision abnormal, hypotension, orthostatic hypotension, hypertension, dyspnoea, upper/lower respiratory tract infection, cough, gastrointestinal haemorrhage (inc mucosal), dyspepsia, abdominal distension, oropharyngeal pain, abdominal pain (inc gastrointestinal and splenic pain), oral disorder, rash, pruritus, muscle spasms, pain in extremity, oedema (inc peripheral), chills, malaise, weight decreased.
Multiple Myeloma: pneumonia, leukopenia, lymphopenia, dehydration, hypocalcaemia, enzyme abnormality, mood disorders & disturbances, anxiety disorder, lethargy, headache, eye swelling, conjunctivitis, vertigo, epistaxis, stomatitis, flatulence, hepatic enzyme abnormality, erythema, dry skin, muscular weakness, renal impairment, pain.
MCL: sepsis (inc septic shock), herpes virus infection, bacterial infections, hypersensitivity, diabetes mellitus, fluid retention, neuropathies, encephalopathy, peripheral sensorimotor neuropathy, autonomic neuropathy, dysacusis (inc tinnitus), cardiac fibrillation (inc atrial), arrhythmia, cardiac failure (inc left and right ventricular), myocardial ischaemia, ventricular dysfunction, hiccups, gastritis, oral ulceration, abdominal discomfort, dysphagia, gastrointestinal inflammation, hepatotoxicity (inc liver disorder), dermatitis, musculoskeletal pain, urinary tract infection, injection site reaction, hyperbilirubinaemia, protein analyses abnormal, weight increased.

Other side effects include: tumour lysis syndrome, pulmonary hypertension, pancytopenia, anaphylactic shock/reaction, hearing impaired (up to and inc deafness), cardiovascular disorder (inc cardiogenic shock), pulmonary embolism, acute respiratory distress syndrome, colitis (inc clostridium difficile), hepatic failure.
Multiple Myeloma: cardiac failure, Posterior Reversible Encephalopathy Syndrome, acute diffuse infiltrative pulmonary disorders, autonomic neuropathy, sepsis, herpes virus infection, meningitis, meningoencephalitis herpetic, Epstein-Barr virus infection, neoplasm malignant, leukaemia plasmacytic, mycosis fungoides, neoplasm benign, lymphadenopathy, febrile neutropenia, thrombotic microangiopathy (including  thrombocytopenic purpura), hypersensitivity, type III immune complex mediated reaction, Cushing's syndrome, mental disorder, suicidal ideation, psychotic disorder, haemorrhage intracranial, peripheral sensory motor neuropathy, encephalopathy, neurotoxicity, cerebral haemorrhage, seizure disorders, paralysis, coma, eye haemorrhage, optic neuropathy, different degrees of visual impairment, cardiac tamponade, cardio-pulmonary arrest, cardiac fibrillation, arrhythmia, tachycardia, angina pectoris, pericarditis, cardiomyopathy, ventricular dysfunction, atrial flutter, myocardial infarction, atrioventricular block, torsade de pointes, angina unstable, cardiac valve disorders, sinus arrest, cerebrovascular accident, deep vein thrombosis, thrombophlebitis, phlebitis, vasculitis, peripheral embolism, pulmonary alveolar haemorrhage, bronchospasm, wheezing, respiratory failure, apnoea, haemoptysis, respiratory alkalosis, throat tightness, pancreatitis, haematemesis, gastro-intestinal obstruction, enteritis, megacolon, peritonitis, gastrointestinal ulceration & perforation, hepatotoxicity, hepatitis, cholestatis, hepatic haemorrhage, acute febrile neutrophilic dermatosis, toxic skin eruption, toxic epidermal necrolysis, Stevens-Johnson syndrome, purpura, erythema multiforme, myopathies, rhabdomyolysis, renal failure, urinary retention, oliguria, death, multi-organ failure, ECG abnormality.
MCL: hepatitis B infection, bronchopneumonia, autonomic nervous system imbalance, vertigo, pneumonitis pulmonary oedema (inc acute).

Refer to SmPC for other side effects.

PREGNANCY:

No clinical data available for bortezomib. Thalidomide contraindicated during pregnancy and in women of childbearing potential unless all conditions of thalidomide pregnancy prevention programme met. Male and female patients of childbearing potential must use effective contraceptive measures during treatment and for 3 months following.

LACTATION:

Not recommended.

INTERACTIONS:

Closely monitor when bortezomib is combined with potent CYP3A4-inhibitors (e.g. ketoconazole, ritonavir). Concomitant use of bortezomib with strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s Wort) not recommended. Hypo/hyperglycaemia reported in diabetic patients receiving oral hypoglycaemics.

LEGAL CATEGORY: POM

PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S) & BASIC NHS COSTS

PRESENTATIONS PACK SIZES MARKETING AUTHORISATION NUMBER BASIC NHS COSTS
3.5 mg vial 1 vial EU/1/04/274/001 £762.38

MARKETING AUTHORISATION HOLDER: JANSSEN-CILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.

FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK.

Prescribing information last revised: February 2019

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